Without a medical practitioner's prescription (ie over the counter (“OTC”)), a full therapeutic dose of paracetamol (acetaminophen) is 1000 mg, a full therapeutic dose of ibuprofen is 400 mg to relieve pain. The total daily amount is also limited to 4000 mg of paracetamol and 1200 mg of ibuprofen, per day in divided doses.
Dosing regimes for each of paracetamol and ibuprofen, when given individually to patients, are often maximised to give the full individual therapeutic dose. Care needs to be taken that the maximum daily dose is met but not exceeded for each medication.
Pharmaceutical combinations such as paracetamol and codeine (500 mg/8 mg) and ibuprofen and codeine (200 mg/12.8 mg) in single dose forms are known. Avoiding use of codeine can be an advantage due to constipation difficulties that are a common side effect.
Combinations of paracetamol, ibuprofen and codeine are known in South Africa, with a single tablet including paracetamol 250 mg, ibuprofen 200 mg, codeine 10 mg. Another combination of paracetamol, aspirin and codeine is also known in a single doss form including 325 mg paracetamol, 325 mg aspirin and 10 mg codeine. In both cases, at a dose of two capsules, sub-therapeutic doses of paracetamol are delivered. In the case of the South African combination, while 4 capsules would give a full OTC therapeutic dose of paracetamol, the amount of ibuprofen would then exceed allowed OTC dose limits.
Paracetamol can be taken without prescription in dosages of 500-1000 mg every 4 to 6 hours up to 4 g/day for the treatment of fever/pain. Ibuprofen is taken without prescription in doses of 200-400 mg every 6 hours up to 1200 mg/day for analgesia.
Ibuprofen is generally well tolerated in divided self medicated doses of up to 1.2 g/day, but it is still associated with side effects in some individuals, such as gastro-intestinal damage. (Reference: Schelman J M et al 2004—A randomised controlled comparison of ibuprofen at maximal over-the-counter dose compared with prescription-dose celecoxib on upper gastrointestinal mucosal injury. Clin Gastroenterol Hepatol 2(4): 290-5) and a a number of other adverse effects (reference: AHFS Drug Information, 2004).
Paracetamol, however, is regarded as “relatively non-toxic in therapeutic doses” (AHFS Drug Information 2004).
The literature has reported that for some drugs the frequency of dosing is more important in determining adverse reactions rather than total dose (I R Edwards, Pharmacological Basis of Adverse Drug Reactions, Chapter 6, page 293 in Avery's Drug Treatment, 1996, 4th edn: Adis International, Auckland). This suggests that giving 2×150 mg ibuprofen four times a day rather than 2×200 mg three times a day may be better tolerated. This type of principle is also in part behind that of sustained release products where drug is gradually released avoiding such extreme peak and trough effects from immediate release dose forms. It is also conceivable that decreasing the amount of ibuprofen given as a single dose will improve the tolerability of ibuprofen.
However, it is a concern that using a lower dose of ibuprofen would result in less pain relief due to a lower peak drug concentrations with the result that the efficacy of the pain relief is reduced.
There would be an advantage to be able to deliver these medications in combination at a high therapeutic dose in order to minimise the number of doses required throughout the day, while still achieving the maximum daily dose rate per day for more effective pain relief. Reduction of the amount of ibuprofen to reduce the likelihood of side effects occurring while maintaining pain relief effect and minimising doses needed would achieve those advantages. The ability to achieve effective pain relief from such a combination to treat short term, intermittent, type pain would also be an advantage. Such a combination has not been previously provided and the concept would allow a number of advantages to be achieved, such as convenience of administration, increased ease of user compliance, and effective pain relief over time.